Cholesteryl ester transfer protein (CETP) as a possible drug-resistance marker in breast cancer

Gu, Liang
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Hormone responsive breast cancer (BC) is the most common BC and relies on steroid hormones for cell proliferation and survival, therefore endocrine therapy; Tamoxifen (TAM), serves as the main therapeutic strategy in treating hormone receptor positive BC. Despite the use of TAM for over four decades, overcoming drug resistance remains challenging. Due to the fact that steroid hormones are derived from cholesterol and evidently, increased level of cholesterol is associated with cancer progression, in this research, we investigated the effect of reducing intracellular cholesterol as a possible alternative method to induce cell death in BC cells. An important protein involved in cholesterol homeostasis is the Cholesteryl Ester Transfer Protein (CETP). CETP maintains cholesterol homeostasis by storing cholesteryl esters (CEs) in lipid droplets. The intracellular accumulation of CEs leads to aggressive cancer development and drug resistance. Therefore, we aim to investigate whether CETP can possibly be used as a drug-resistance marker in BC. This study has shown that knocking-down CETP resulted in increase in apoptosis in MCF-7 cells when treated with TAM (by 10-40%) and various other drugs. Furthermore, CETP knock-down with the addition of a cholesterol-depleting agent increased apoptosis by 10 fold when compared to the non-transfected MCF-7 cells, possibly due to a decrease in CE content. Similar results were observed in MDA-MB-231 cells. Therefore, it was concluded that CETP could thus serve as a potential drug-resistance marker in cancer cells, more specifically BC. Furthermore, strategies targeting CETP could be used as a potential combination treatment for treating cancer.
A research dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in the fulfilment of the requirements for the Degree of Masters in Science, Signed on 24 May 2018 in Johannesburg
Gu, Liang (2018) Cholesteryl ester transfer protein (CETP) as a possible drug-resistance marker in breast cancer, University of the Witwatersrand, Johannesburg,